15-Deoxy-16-hydroxy-16-chloromethyl or bromomethyl prostaglandins of the E and F series

ABSTRACT

The invention disclosed herein relates to pharmacologically active prostaglandins of the E and F series in which C-16 is substituted with hydroxyl and chloromethyl or bromomethyl as well as the pharmacologically acceptable, nontoxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to 15-deoxy-16-hydroxy-16-chloromethyl and 16-bromomethyl prostaglandins, as well as the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.

(2) Description of the Prior Art

Prostaglandins have classically been described as chemically related 20 carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acid: ##STR1##

The prostaglandins having a hydroxyl group at the C-11 position and a keto group at the C-9 position are known as the PGE series, and those having a hydroxyl group in place of the keto group are known as the PGF series and are further designated by an α or β suffix to indicate the configuration of the hydroxyl group at said position. The natural compounds are the α-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5, C-13 and C-17, the unsaturation is also indicated by a suffix. Thus, for example, the PGF₁ and PGE₁ series refer to prostanoic acids having a trans olefin bond at the C-13 position, while the PGF₂ and PGE₂ series refer to prostadienoic acids having a cis-olefin bond at the C-5 position and a trans olefin bond at the C-13 position. For a review on prostaglandins and the definition of primary prostaglandins, see, for example, P. Ramwell, The Prostaglandins, 1, pp. 5-22 (1973).

The preparation of derivatives of prostanoic acid has become of great importance since the demonstration of the highly interesting range of biological and pharmacological activities of natural prostaglandins.

The great majority of these studies have focused on modification of the two side chains, or modifications of the substituents attached to the cyclopentane moiety [see for example U. Axen et al., Synthesis Vol. 1, John Wiley and Sons Inc., New York, New York, 1973 and P. H. Bently, Chem. Soc. Reviews, 2, 29 (1973)].

The synthesis of prostaglandin analogs possessing a 3-oxa- or 11-deoxy-3-thia moiety have been described, among others in U.S. Pat. No. 3,873,607; U.S. Pat. No. 3,950,406; Netherlands Pat. No. 7305222-Q; U.S. Pat. No. 3,944,593; U.S. Pat. No. 3,931,289; and U.S. Pat. No. 3,936,487.

The synthesis of several prostaglandin analogs wherein the hydroxyl group at C-15 has been removed and a hydroxyl group has been introduced at C-16 has appeared [see for example, U.S. Pat. No. 3,950,406; Prostaglandins, Vol. 10, 733 (1975); Tetrahedron Letters, No. 48, 4217 (1975)].

Recently, reports have also appeared wherein the C-16 carbon bearing a hydroxyl group is substituted with a methyl group [see Pappo et al., Tetrahedron Letters, No. 4, 235 (1975); Collins et al., U.S. Pat. No. 3,965,143; and Belgium Pat. No. 827,127].

Also, a patent has recently appeared wherein the C-16 carbon bearing the hydroxyl group is substituted with vinyl, methylvinyl, and cyclopropyl (U.S. Pat. No. 4,061,670).

SUMMARY OF THE PRESENT INVENTION

In accordance with the present invention, we have prepared certain novel 15-deoxy-16-hydroxy-16-chloromethyl and 16-bromomethyl-prostaglandin analogs represented by the following formula: ##STR2## wherein Y is ##STR3## R₁ is selected from the group consisting of hydrogen and hydroxyl; R₂ is selected from the group consisting of hydrogen and C₁ -C₆ alkyl;

R₃ is selected from the group consisting of chloromethyl and bromomethyl, preferably chloromethyl;

R₄ is selected from the group consisting of hydrogen and C₁ -C₃ alkyl;

Z is selected from the group consisting of a divalent moiety of the formulae: --(CH₂)_(n) --, --(CH₂)_(m) OCH₂ --, --(CH₂)_(m) SCH₂ --, and ##STR4## wherein m is 3 to 5, preferably 4, n is 5 to 7, preferably 6, and p is 2 to 4, preferably 3; the racemic mixture thereof; and when R₁ is hydrogen, the pharmacologically acceptable salts thereof.

The dotted lines shown in the above formula and in the formulas below indicate that the substituents are in configuration, i.e., below the plane of the cyclopentane ring.

The double bond at C-13 in the compounds of the present invention has the same configuration as in natural prostaglandins of the PGE and PGF series, that is the trans configuration.

These novel compounds possess asymmetric centers and thus can be produced as racemic mixtures or as individual enantiomers. The racemic mixtures can be resolved if desired at appropriate stages by methods known to those skilled in the art, to obtain the respective individual enantiomers. It is to be understood that the racemic mixtures and the individual 8R-enantiomers are encompassed within the scope of the present invention.

When the compounds of the present invention are racemic mixtures, they are produced starting from racemates, while when the compounds of the invention are individual enantiomers the compounds are preferably obtained starting from the appropriate individual enantiomer.

Useful pharmacologically acceptable salts of the above formula, where R₁ is hydrogen, are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, tri-isopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- or β-phenyethylamine, ethylenediamine, and arylipatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g. mono- , di-, or triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-(p-tertamylphenyl)-diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

The novel compounds of this invention can be prepared by a 1,4-conjugate-addition procedure involving treatment of the ether blocked cyclopentenone (14) with a lithiocuprate reagent such as (11), (12), or (13) prepared as illustrated in Flowsheets A, B, C and D.

Although Flowsheets A and B exemplify the use of a trimethylsilyloxy protecting group, any protecting groups which survive the conjugate addition reaction described by these tables and the examples of this application may be employed. Suitable protecting groups, therefore, include tri--(C₁ -C₄)--alkylsilyl, or other acid labile protecting groups such as tetrahydropyranyl, tetrahydrofuranyl or other acetals. Moreover, with reference to the lithio cuprates of Flowsheet B (structures 8, 9 or 10) in addition to the lithio cuprates described, the lithio cuprates of structure 15 may also be employed. ##STR5##

In accordance with the procedure outlined in Flowsheet A, treatment of a carboxylic acid halide such as (1), wherein R₄ is hydrogen, methyl, ethyl or propyl, with 1,1,2-tris-trimethylsilyloxyethylene (2), [Tet. Letters, (1978)] provide the α-hydroxyketone (2). Treatment of (3) with methanesulfonylchloride in dimethylformamide (DMF) provides the α-chloroketone (4).

In accordance with Flowsheet B, treatment of the α-haloketones (5) with propargylmagnesium bromide in the presence of mercuric chloride provides the hydroxyalkyne (6) that is treated with a trialkylchlorosilane such as chlorotrimethylsilane to provide the ether (7). The alkyne (7) is treated with tri-n-butylstannane in the presence of azobisisobutylnitrile (AIBN) to provide the trans-vinylstannane containing 10 to 20% of the corresponding cis isomer (9). Lithiation then provides the vinyllithium reagent (10). ##STR6##

In accordance with Flowsheet C, for the preparation of the asymmetrical lithio-cuprate (11) wherein R₃ is CH₂ Cl or CH₂ Br, a solution of one molar equivalent of copper (I)-1-alkyne, preferably copper (I)-1-pentyne in anhydrous tributylphosphine or HMPTA, preferably one to five molar equivalents, in ether is added to one molar equivalent of the aforementioned vinyl lithium solution cooled to about -78° C. After about one hour at this temperature, a molar equivalent of the requisite cyclopentenone (14) is added. After several hours at -30° C. to -70° C. the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (15) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with the asymmetrical lithio cuprate (13) wherein R₃ is as previously defined derived from vinyl lithium and cuprous thiophenoxide. A solution of vinyl lithium (10) in ether at -78° C. is reacted with an equimolar amount of a reagent prepared by admixture, in ether at a temperature of 0° C. to -78° C., of equimolar amounts of cuprous thiopenoxide and copper (I) iodide tributylphosphonium complex. After about 30 minutes at this temperature, the lithio-cuprate (13) is treated with the requisite cyclopentenone (14) as described hereinabove for the conjugate addition with 1-alkynyl lithio-cuprate (11).

For the preparation of the symmetrical lithio-cuprate (12) wherein R₃ is as previously defined one molar equivalent of copper (I) iodide tributylphosphine complex, dissolved in anhydrous ether, is added at about -78° C. to two molar equivalents of the aforementioned vinyl lithium (10) solution cooled to -78° C. After about one hour at this temperature, the lithio-cuprate (12) is treated with the requisite cyclopentenone (14) as described hereinabove for the conjugate addition with the 1-alkynyl lithio-cuprate (11).

The procedures for conjugate addition involving organocopper reagents are well known in the art, see for example C. J. Sih, et al., J. Amer. Chem. Soc., 97, 865 (1975) which is incorporated by reference.

In the cases where R'₁ =trimethylsilyloxy in cyclopentenone (14) the conjugate addition is performed at -78° C. to -40° C. The reaction is quenched by addition of an ether solution of acetic acid. Removal of blocking groups is then carried out as described in the reference above to provide the product (16) wherein R₁, R₂, R₃ and R₄ are as hereinabove.

The introduction of a racemic β-chain possessing the 16-hydroxy-16-chloromethyl and bromomethyl groups provides a pair of prostaglandins epimeric at C-16. These two epimers may be separated into their upper (less polar) and lower (more polar) components by high-pressure liquid chromatography (HPLC) or by dry-column or preparative thin layer silica-gel chromatography.

If an optically active protected cyclopentenone such as (14) is utilized, then HPLC separation will provide the corresponding optically active nat. 9-oxo-11α,16α-dihydroxy-16-chloromethyl or bromomethyl and nat. 9-oxo-11α,16β-dihydroxy-16-chloromethyl or bromomethyl-PGE enantiomers.

All available evidence leads us to believe that the ##STR7## function introduced by the cuprate process occupies a position trans to the 11-oxy function. Similarly, we are led to the conclusion that in the product (16) the two side-chains attached to C₈ and C₁₂ are trans to each other. However, we are not certain of this configurational relationship in the product as it is obtained directly from the cuprate process. These products may have the side-chains in a trans- or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8 ξ. In order to ensure a trans-relationship in (16) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE₁ to a mixture containing about 90% of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The triloweralkylsilyloxy substituted lithio cuprate reagents of type (10) and trialkylstannyl precursors are novel and useful compounds which are also embraced by this invention. They may be defined by generic formulae (17) and (18). ##STR8## wherein W is R-Sn, wherein R is tri-(C₁ -C₆)-alkyl and preferably a tri-n-butyl group, or W is lithium, R₈ is tri-C₁ -C₄ alkylsilyl, preferably trimethylsilyl or other acid labile protecting groups such as tetrahydropyranyl, tetrahydrofuranyl or other acetals, R₉ is thiophenoxide, substituted thiophenoxide wherein the substitutent may be C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₃ dialkylamino or phenyl, or R₉ may be C₃ -C₄ alkyne or the identical vinyl moiety in addition to the lithiocuprates described, the lithiocuprates of structure 15 may also be employed.

The cyclopentenones required for the preparation of the E₁, E₂, 3-oxa, and 11-deoxy-3-thia series have been described in the literature. The cyclopentenone for the preparation of 3-thia-11-hydroxy prostaglandins is described in Flowsheet D.

In accordance with Flowsheet D which is hereinbelow described, treatment of 2-furyl lithium (19) with a ω-chloroaldehyde (20) provides the chloroalcohol (21). Treatment of the chloroalcohol (21) with ethylmercaptoacetate furnishes the hydroxyester (22) which upon hydrolysis with sodium formate/formic acid provides the 3-hydroxy-cyclopentenone (23). Treatment of the cyclopentenone (23) with sulfuric acid provides the required 4-hydroxy-cyclopentenone (24) which after treatment with chlorotrimethylsilane provides the bissilylated cyclopentenone (25). ##STR9##

In accordance with Flowsheet E, when the 11-hydroxy or 11-oxy derivatives are treated with dilute acid, it is possible to effect elimination and the formation of the corresponding Δ¹⁰ derivatives (26) of the prostaglandin A-type. A preferred procedure involves treatment in tetrahydrofuran:-water (2:1) solvent 0.5N in HCl for about 30 hours at ambient temperature. Under these conditions a tetrahydropyranyl or trialkylsilyl ester or ether will undergo hydrolysis. ##STR10##

The prostaglandin carboxylic acids of this invention can be readily converted to the various alkyl esters of this invention by treatment in the usual manner with the appropriate diazoalkane. The preparation of diazoalkanes by various procedures are well described in the art. See for example, C. D. Gutsche, Organic Reactions, VIII, 389 (1954). Certain of the esters of this invention can also be obtained directly by use of the appropriate cyclopentenone ester. The various esters can also be prepared by any of several procedures well-known in the art via an acid chloride (prior blocking of free alcohol groups with appropriate blocking groups such as trialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides and treatment of these intermediates with the appropriate alcohol. Mixed anhydrides can be obtained by treatment of the prostaglandin acid in a solvent such as dioxane at a temperature in the range of 0° C. to 15° C. with a molar equivalent of a tri-alkylamine, preferably triethylamine, tributylamine and the like, and then a molar equivalent of isobutyl chlorocarbonate or the like. The resulting mixed anhydrides are then treated with the appropriate alcohol to give the derivatized product. [For a pertinent literature analogy see Prostaglandins, 4, 768 (1973).]

An alternative procedure involves treatment of the prostaglandin acid with a molar equivalent of the trialkyl amine in an excess of the appropriate alochol in an anhydrous solvent such as methylene chloride, molar equivalent of p-toluenesulfonyl chloride is then added (if necessary, a second molar equivalent can be added) and after stirring at ambient temperatures for about 15 minutes to one hour and product is worked-up in the usual manner. (For a pertinent literature analogy, see U.S. Pat. No. 3,821,279). A third procedure involves the use of dicyclohexylcarbodiimide in the usual manner; for a pertinent literature analogy see German Offen. No. 2,365,205; Che. Abst., 81, 120098g (1974).

The esterified alcohol derivatives of this invention are also prepared in the usual manner by procedures well known in the art from the appropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic starting compounds, two racemates are obtained. In appropriate instances these racemates may be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (Aug. 1973) as well as references cited therein. Additional information, concerning high speed liquid chromatography and the instruments necessary for its application, is available from Waters Associate Inc., Maple Street, Milford, Mass.]. ##STR11##

In accordance with Flowsheet F treatment of a prostaglandin of the E series (9-oxo) (16) with a carbonyl reducing reagent such as sodium borohydride provides a mixture of the corresponding PGFα (9α-hydroxy) (27) and PGFβ (9β-hydroxy) (28) analogs. These two epimeric alcohols are readily separated by silica gel chromatography.

If one utilized the individual 16α-hydroxy or 16β-hydroxy (27) starting material, the isolated products are the 9α,16α-dihydroxy and 9α,16β-dihydroxy derivatives, respectively.

Use of a stereoselective reagent such as lithium-perhydro-9b-boraphenalylhydride [H. C. Brown and W. C. Dickason, J.A.S.C., 92, 709 (1970)] or lithium tri-sec-butylborohydride [H. C. Brown and S. Krishnamurthy, Ibid, 94, 7159 (1972)] provides the PGFα product as the selective species.

Likewise, utilization of either the individual 16α- or 16β-hydroxy (27) compounds affords the corresponding 9α,16α-di-hydroxy and 9α,16β-dihydroxy prostaglandins of this invention. ##STR12##

In accordance with Flowsheet G when 11α-hydroxy-PGF₂ α congeners such as (27) are treated with an oxidizing reagent such as Jones Reagent, or pyridinium chlorochromate provides a selective oxidation to give the corresponding PGD derivative (9-hydroxy-11-keto) (29) which is isolated after chromatographic purification.

If one utilized the individual 16α-hydroxy or 16β-hydroxy PGFα derivative of (27), then the corresponding 9α,16α-dihydroxy-11-oxo and 9α,16β-dihydroxy-11-oxo-prostaglandins are isolated, respectively.

In the following formulae Z is as hereinabove defined.

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (31) and (32) wherein Z is as hereinabove defined by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereoisomeric mixture can then be separated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are 1-α-aminoxy-α-methylpentanoic acid hydrochloride (to give (30)), (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-α-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (31) and (32). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (30) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973)]. The resolution of the hydroxycyclopentenone (22) wherein Z is ##STR13## is described by Bruhn et al., Tetrahedron Letters, 235 (1976). ##STR14##

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and other gastric difficulties associated with the use of various nonsteroidal anti-inflammatory agents (e.g., indomethacin, aspirin, and phenylbutazone), bronchodilators, anti-inflammatory agents, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, oestrus regulators for use in animal husbandry with cattle and other domestic animals and central nervous system regulatory agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of the other novel compounds of this invention.

The novel compounds of this invention possess the pharmacological activity described below as associated with the appropriate above-described prostaglandin types.

The known PGE, PGF₆₀, PGF₆₂, PGA and PGD compounds are all potent in causing multiple biological responses even at low doses. For example, PGE₁, PGE₂, PGA₁ and PGA₂ are extremely potent in causing vasodepression and smooth muscle stimulation, and also are potent as antilipolytic agents. For example, the 11-deoxy-PGE compounds of this invention are selective in that they are at most relatively weak stimulants of smooth muscle. A further advantage of these novel compounds lies in their increased stabilities and lengthened shelf-lives.

Therefore, each of these novel prostaglandin analogs of this invention is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological puroposes indicated below for the latter, either because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandins, or because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

Another advantage of the novel compounds of this invention, compared with the known prostaglandins, is that these novel compounds are administered effectively orally, sublingually, intravaginally, buccally, or rectally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

PGE₁, PGE₂, PGE₃, dihydro-PGE₁, PGF.sub.α, PGF.sub.β and PGA compounds, their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrome, et al., Pharmacol. Rev., 20, 1 (1968), and references cited herein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGA and PGE compounds as measured, for example, in anesthetized (sodium phenobarbital) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the PGF compounds; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE compounds, as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness in the case of PGE, as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen, and in the case of the PGE and PGA compounds, stimulation of epidermal proliferation and keratinization, as shown when they are applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of disease and undesirabe physiological conditions in birds and mammals including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, e.g., mice, rats, rabbits, and monkeys.

For example, these compounds are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 mg to about 10 mg per ml of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

PGA, PGF.sub.β and PGE compounds are useful as hypotensive agents to reduce blood pressure in mammals including man. For this purpose, the PGF.sub.β compounds are administered by intravenous infusion at the rate of about 0.01 mg to about 40 mg per Kg of body weight per minute, or in a single dosage or multiple doses of about 25 mg to 2500 mg per Kg of body weight total per day. The PGE and PGA compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 mg per Kg of body weight per minute, or in a single dose or multiple doses of about 25 to 2500 mg per Kg of body weight total per day.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful in place of oxytocin to induce labor in pregnant female animals, including humans, cows, sheep and pigs, at or near term or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the PGF compound is infused intravenouslyat a dose of 0.01 mg to 50 mg per Kg of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. Similarly, the PGE compound is infused intravenously at a dose of 0.01 to 50 mg per Kg of body weight per minute until or near the expulsion of the fetus. These compounds are especially useful when the female is one or more weeks postmature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.

The PGE, PGF.sub.α and PFG.sub.β compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and other animals. For that purpose, PGF₂α, for example, is administered systemically at a dose level in the range of 0.01 mg to about 20 mg per Kg of body weight, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Likewise, a PGE compound is administered in the same fashion at a dose level of 0.01 mg to about 50 mg per Kg of body weight. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third or the second third of the normal mammalian gestation period. Accordingly, such compounds are useful as abortifacients. They are also useful for induction of menses during approximately the first two weeks of a missed menstrual period and thus, are useful as contraceptive anti-fertility agents.

11α-hydroxy-PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE₂, for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators for example, to relieve the symptoms of paralytic ileus, to control or prevent uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 mg per Kg of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to 2 mg per Kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The novel PGA, PGE and PGF.sub.β of this invention are also useful as bronchodilators for the treatment of asthma and chronic bronchitis. As such they may be conveniently administered by inhalation of aerosol sprays prepared in a dose range of about 10 μg to about 10 mg/ml of a pharmacologically suitable liquid vehicle. Relative to the natural prostaglandins, the PGA and PGE compounds in particular have the significant advantage of inducing prolonged effects.

The PGE and PGA compounds are also useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastric erosion or gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of about 0.1 mg to about 500 mg per Kg of body weight per minute, or in a total daily dose by injection or infusion in the range of about 0.1 to about 20 mg per Kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. These compounds may also be useful in conjunction with various non-steroidal anti-inflammatory agents, such as aspirin, phenylbutazone, indomethacin and the like, to minimize the well-known ulcerogenic effects of the latter.

The PGE and PGA compounds also stimulate epidermal proliferation and keratinization, and in such a capacity are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, abrasions or surgery. The nasopressor action of the PGA compounds makes them particularly useful in speeding the adherence and growth of skin autografts, especially small, deep (Davies) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and in retarding rejection of homografts.

For these purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion cream, or ointment in combination with the usual pharamaceutically acceptable diluents. In some instances, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration of PGE is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. Illustrative of a wet dressing for topical application to second and/or third degree burns of skin area 5to 25 square centimeters is the use of an isotonic aqueous solution containing one to 500 mg/ml of the PGA compound or several times that concentration of the PGE compound. Especially for topical use, these prostaglandins are useful in combination with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticoid steroids, such as hydrocortisone, prednisolone, methylprednisolone, and fluoroprednisolone; each of those being used in the combination at the usual concentration suitable for its use alone.

The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing the volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal disfunction, especially in cases of severely impaired renal blood flow, for example, the hepatorena syndrome and early kidney transplant rejection. In case of excessive or inappropriate antidiuretic hormone ADH vasopressin secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful.

The PGE compounds of this invention are also useful as topical vasodilators.

The PGE₁ compounds of this invention are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals including man, rabbits, and rats. For example, these compounds are useful to treat and prevent myocardial infarcts and post-operative thrombosis. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range of about 0.005 to about 20 mg per Kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

It is well known that platelet aggregation inhibitors may be useful as anti-thrombotic drugs. Inhibition of platelet aggregation can be conveniently measured in vitro by monitoring changes in optical density and/or light transmission in platelet rich plasma upon addition of suitable aggregating agents such as adenosine diphosphate, epinephrine, thrombin or collagen. Alternatively, platelet aggregation can be measured in vitro using platelet rich plasma obtained at various time intervals from animals given inhibitors by an oral or parenteral route.

The PGE compounds of the present invention exhibit the ability to inhibit platelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solution in a proportion of 40-50% human protein rich plasma. The test compounds are added at varying concentrations and after 5 minutes incubation, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (light transmission) is monitored by eye and inhibition is recorded as a (-) or lack of inhibition is recorded as a (+). Test compounds are considered active if they inhibit adenosine diphosphate or collagen induced aggregation at a concentration of 0.025 mg/ml or less within 5-10 minutes.

The PGE compounds of this invention also have bronchodilator activity as determined in a test using dogs anesthetized, artificially ventilated and submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. They are premedicated with morphine HCl by subcutaneous injection at 1.5 mg/Kg. An intravenous perfusion of 5% (W/V) chloralose is started 1/2 hour after the morphine injection in such a way that 60 mg/Kg are administered within 15 minutes. After completion, a continuous perfusion of 10 mg/Kg/hour is maintained throughout the experiment. The dogs are artificially ventilated by means of a Starling pump at a rate of 20 breaths/minute. The volume is adjusted according to the weight of the animal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. All the measurements are made with the dogs positioned supine in a heated, V-shaped table. Curarization is obtained by succinylcholine chloride using a starting injection of 3 mg/Kg lasting 3 minutes, followed by a continuous perfusion of 0.1 mg/Kg/minute.

The respiratory spasm is induced by a starting injection of 400 μg/Kg of pilocarpine HCl lasting 5 minutes. An increase or decrease in the dose of pilocarpine HCl may occur as a function of the observed effect on the airway's resistance. A 15 minute delay is observed before the start of a continuous perfusion of pilocarpine HCl at a dose of 4 μg/Kg/minute to maintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into the upper part of the trachea. The two cephalic veins and the two femoral veins are catheterized to inject the various agents. The femoral artery is catheterized to measure the systemic blood pressure. An esophageal balloon (11 cm × 2.5 cm) is inserted into the lower third of the oesophagus to measure the endothoracic pressure. The measurement of air flow is made with a Fleish pneumotachograph connected to the tracheal tube.

The transpulmonary pressure is measured as follows: The tracheal cannula is equipped with a stainless steel axial tube (1.5 mm) which is closed at its distal end and projected 2.5 cm beyond the end of the cannula. Three holes with a diameter of one mm are pierced on this latter segment. This tube, which is used to measure the tracheal pressure, is connected to one of the two chambers of a Sanborn 267 B/C differential transducer. The other chamber is connected to the esophageal ballon by means of a polyethylene catheter of the same length and characteristics as the balloon's.

The airflow is measured from the Fleish pneumotachograph by means of a Sanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flow signal using an R.C. integrator.

The systemic and pulmonary blood pressures are gauged by means of a Sanborn 267 B/C or 1280B pressure transducer.

An electrocardiogram is taken in lead 2. Its use is to monitor a cardiac rate-meter.

All these parameters are recorded on a Sanborn polygraph. The transpulmonary pressure and the tidal volume are also displayed as rectangular coordinates on an oscilloscope.

The airway's resistance, expressed in cm of water/liter/second, is measured by subtracting from the electrical equivalent of the transpulmonary pressure, a voltage proportional to the flow so as to synchronize the pressure and volume signals on the oscilloscope [Mead and Whittenberger, J. Appl. Physiol., 5, 779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, is obtained by means of the same principle, i.e., an electrical signal proportioned to the volume is subtracted from the transpulmonary pressure signal, in order to optimize the pressure-flow loop on the oscilloscope.

The details of this method are described by Lulling, et al. [Med. Pharmacol. Exp., 16, 481 (1967)].

The computing operations are carried out with an analogical computer which allows the direct reading, cycle to cycle, of the values of resistance and elastance.

The test compounds are administered by an Aerosol® route. The micronebulizer of a Bird Mark 7 respirator is fitted on the metallic cannula just after the pneumotachograph. The "puff" of the test compound, in Aerosol® is driven by a 2 Kg/cm₂ pressure, allowed into the micronebulizer just during one inspiration cycle. The micronebulizer is fitted on the respiratory tube only during the "puff." It is weighed just before and just after administration to determine the amount of test compound administered. Approximately 50 mg of the solution is administered to each dog. In accordance with the Pilocarpine Assay described herein, the compounds of this invention should exhibit bronchodilator activity.

The bronchodilator activity for representative compounds of this invention was determined in Guinea-Pigs against bronchospasms elicited by intravenous injections of serotonin, histamine, and acetylcholine, by the Konzett procedure the details of which are those discussed by J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzeimittel-Forschung 18, 995 (1968).

REFERENCE EXAMPLE 1 1-Hydroxy-2-hexanone

To a stirred mixture of 25 g. of valeryl chloride and 122.6 g. of tris(trimethylsilyloxy)ethylene is added 9 drops of anhydrous stannic chloride. After stirring at room temperature for 1.5 hours, the mixture is poured slowly into a stirring mixture of 60 ml of 0.6 N hydrochloric acid and 120 ml. of tetrahydrofuran and stirred for one hour. Work up is by diluting with ether, washing with brine, saturated sodium bicarbonate and brine again, and drying over anhydrous sodium sulfate. The ether solution is evaporated to dryness to give 21.5 g. of liquid which is vacuum distilled to give 15.5 g. of colorless liquid at b.p. 70°-77° C./9 mm.; PMR δ 4.28 (s), 2.42 (t, J=6).

REFERENCE EXAMPLE 2 1-Chloro-2-hexanone

To a stirred solution of 11.5 g. of 1-hydroxy-2-hexanone in 110 ml. of dimethylformamide is added 35 ml. of methanesulfonyl chloride dropwise during 10 minutes. The mixture is heated and stirred at 85° C. for 3 hours, then cooled in a ice-water bath. To this is added 50 ml. of water dropwise and the mixture is extracted with ether. The ether solution is washed with water and brine, dried, and then distilled to give 10.8 g. of product as a colorless liquid at b.p. 30°-32° C./4 mm.; PMR δ 4.12 (s), 2.60 (t, J=7).

REFERENCE EXAMPLE 3 4-Chloromethyl-4-hydroxy-1-octyne

To a stirred suspension of 2.1 g. of magnesium and 20 mg. of mercuric chloride in 25 ml. of ether is added 0.8 ml. of propargyl bromide. After a few minutes of vigorous stirring, to this is added a mixture of 10.75 g. of 1-chloro-2-hexanone and 7.2 ml. of propargyl bromide in 25 ml. of ether, at such a rate that the reaction mixture is maintained at 25°-28° C. After addition, the mixture is stirred at room temperature one hour, cooled in a ice-water bath and 30 ml. of saturated ammonium chloride is added dropwise. The mixture is filtered through celite and washed with ether. The ether solution is concentrated to give 11.0 g. of a yellow liquid which is vacuum distilled to give 6.9 g. of product as a colorless liquid at b.p. 60°-61° C./4 mm.; PMR δ 3.62 (ABq, CH₂ Cl), 2.53 (d, J=3, C.tbd.C--CH₂), 2.06 (t, J=3, HC.tbd.C).

REFERENCE EXAMPLE 4 4-Chloromethyl-4-trimethylsiloxy-1-octyne

To a stirred, ice-cold solution of 7.22 g. of 4-chloromethyl-4-hydroxy-1-octyne and 7.16 g. of imidazole in 28 ml. of dimethylformamide is added 6.5 ml. of trimethylchlorosilane via a syringe during 15 minutes. The resulting mixture is stirred at room temperature overnight, diluted with hexane and poured into a mixture of ice and saturated sodium bicarbonate solution. The hexane solution is separated, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 11.8 g. of a colorless liquid which is vacuum distilled at b.p. 50°-57° C./3.5-4 mm. to give 9.7 g. of product as a colorless liquid; PMR δ 3.58 (s), 2.50 (d), 1.99 (t), 0.87 (s, OTMS).

REFERENCE EXAMPLE 5 1-Tri-n-butylstannyl-4-chloromethyl-4-trimethylsiloxy-trans-1-octene

A mixture of 9.27 g. of 4-chloromethyl-4-trimethylsilyloxy-1-octyne, 40 mg. of azoisobutyronitrile, and 10.0 ml. of tri-n-butyltin hydride is heated and stirred at 125° C. for 1.5 hours, then vacuum distilled through a short path to give, after a forerun, 19.5 g. of product as a colorless liquid at b.p. 140-160° C./0.1-0.2 mm.; PMR δ 5.98 (m, olefin), 3.40 (s, CH₂ Cl), 2.40 (m, C═C--CH₂), 0.14 (s, OTMS).

REFERENCE EXAMPLE 6 1,9-Dioxo-1-hydroxymethyl-11α, 16α-dihydroxy-16-chloromethyl-13-trans-prostene and 1,9-dioxo-1-hydroxymethyl-11α, 16β-dihydroxy-17-chloromethyl-13-trans-prostene

To a stirred solution of 5.56 g. of E-1-tri-n-butylstannyl-4-trimethylsilyloxy-4-chloromethyl-1-octene in 6 ml. of tetrahydrofuran, cooled in a dry ice-acetone bath, is added 4.7 ml. of n-butyl lithium (2.2 M in hexane) during 30 minutes. After stirring at -45° C. for 45 minutes, then at -30° C. for 30 minutes, it is recooled to -78° C. and there is added a solution of 1.35 g. of 1-pentynyl copper and 3.7 ml. of hexamethylphosphoroustriamid in 10 ml. of ether. After stirring at -78° C.for 1.5 hours the resulting mixed cuprate solution is added to a solution of 2.0 g. of protected cylopentenone (ref. ex. 14) in 5 ml. of ether during 20 minutes. After stirring at -45° C. for one hour, then at -30° C. for 20 minutes it is recooled to -70° C. and quenched by pouring into a cold mixture of 200 ml. of saturated ammonium chloride, 3 ml. of acetic acid and 200 ml. of ether. The organic phase is separated and washed with dilute hydrochloric acid, water and brine and concentrated to give a liquid. The liquid is treated with 30 ml. of acetic acid, 15 ml. of tetrahydrofuran and 7.5 ml. of water and stirred at 40° C. for one hour. It is diluted with toluene and rotary evaporated to dryness to give an amber oil. The oil is applied to a pad of silica gel (25 g. of silic ARCC-7) and washed with 200 ml. of hexane followed by 200 ml. of ethyl acetate. The ethyl acetate solution is concentrated to give 3.7 g. of amber oil which is purified by dry column chromatography (870 g. silica gel) to give 0.98 g. of pure product as a yellow oil; PMR δ 5.56 (m, olefin), 4.24 (s, CH₂ OH), 4.06 (q, J=6, 11-H).

REFERENCE EXAMPLE 7 Preparation and Separation of 9α, 11α,16-trihydroxy-16-chloromethyl-5-cis,13-trans-protadienoic acid and 9β,11α,16-trihydroxy-16-chloromethyl-5-cis, 13-trans-prostadienoic acid

To a stirred, ice-cold solution of 9-oxo-11α,16-dihydroxy-16-chloromethyl-5-cis,13-trans-prostadienoic acid in ethanol is added excess sodium borohydride in small portions during 1 minute. The mixture is stirred at 0° C. for 5 minutes and at ambient temperature for 1.5 hours. The bulk of the ethanol is evaporated in vacuo at room temperature and the residue is partitioned with cold, very dilute, hydrochloric acid and ethyl acetate. The organic phase is evaporated and washed with water and brine and dried over magnesium sulfate and concentrated in vacuo.

The residue is subjected to silica-gel chromatography to give: first eluted-9α,11α,16-trihydroxy-16-chloromethyl-5-cis,13-trans-prostadienoic acid followed by 9β,11α,16-trihydroxy-16-chloromethyl-5-cis,13-trans-prostedienoic acid.

If one starts with the individual 16α or 16β-hydroxy isomer, then the corresponding products will also be 16α or 16β-hydroxy, respectively.

REFERENCE EXAMPLE 8 Preparation of 9α,11α,16-trihydroxy-16-chloromethyl-5-cis,13-trans-prostadienoic acid

To a stirred solution of 9-oxo-11α,16-dihydroxy-16-chloromethyl-5-cis,13-trans-prostadienoic acid in tetrahydrofuran (THF) at -78° C. is added in excess of a 0.5 M solution of lithium perhydro-9β-boraphenalyl hydroxide in THF. After 30 minutes at -78° C., the solution is warmed to 0° C. and treated with water. This mixture is partitioned with ether-potassium carbonate solutions. The aqueous phase is carefully acidified with hydrochloric acid, saturated with NaCl, and extracted with ethyl acetate. The organic extract is washed with brine, dried with magnesium sulfate, and concentrated in vacuo.

The residue is subjected to silica gel dry column chromatography to provide 9α,11α,16-trihydroxy-16-chromomethyl-5-cis,13-trans-prostadienoic acid which may be separated into the individual 16α-and 16β-hydroxyl isomers by HPLC techniques.

REFERENCE EXAMPLE 9 Preparation of 9-oxo-16-hydroxy-16 chloromethyl-5-cis,10,13-trans-prostatrienoic acid 9-Oxo-11α,16-dihydroxy-16-chloromethyl-5-cis,13-transprostadienoic acid is dissolved in a 1:1 tetrahydrofuran water mixture containing 0.5N HCL and allowed to stand at ambient temperature under argon for 72 hours. The solution is treated with brine and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to an oil. This residue is purified by dry column chromatography to give 9-oxo-16-hydroxy-16-chloromethyl-5-cis,10,13-trans-prostatrienoic acid. If one utilizes the individual 16α or 16β isomer, the product obtained is the 16α or 16β epimer, respectively. REFERENCE EXAMPLE 10 Preparation of 9α,16-dihydroxy-11 -oxo-16-chloromethyl5-cis,13-trans-prostadienoic acid

To a solution of 9α,11α,16-trihydroxy-16-chloromethyl-5-cis-,13-trans-prostadienoic acid in acetone (12 ml/g.) at -35° C. is added, dropwise, with stirring, one equivalent of Jones reagent (2.67 g CrO₃ and 2.3 ml of concentrated H₂ SO₄ diluted to 10 ml with water). After 15 minutes isopropanol is added, followed by water. The mixture is poured into water, saturated with NaCl, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo to an oil.

This oil is chromatographed on a dry column of silica-gel using ethyl acetate/heptane mixtures containing 1% acetic acid, to provide the product above.

If one starts with either of the individual 16α or 16β-hydroxyl isomers, one isolates the 16α or 16β-hydroxyl isomers, respectively.

REFERENCE EXAMPLE 11 Preparation of 2-(6-carbodimethyl-t-butylsilyloxyhexyl)-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-1-one

To a stirred 35° C. solution of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one (33.1g, 146 mmol) in dimethylformamide (100 ml) is added imidazole (48 g, 77 mmol) followed immediately by a slurry of t-butyl:chlorodimethylsilane (48.2 g, 321 mmol) in dimethylformamide (45 ml). The resulting mixture is stirred under nitrogen atmosphere at 55° C. After 4 hours the cooled mixture (2 layers) is treated with hexane (400 ml) and water (150 ml). The hexane layer is separated and washed twice with water (100 ml each time) and twice with saturated sodium chloride solution (100 ml each time) and dried over magnesium sulfate. The solvent is removed in vacuo at 50° C.to give 66 g of a mobile amber liquid. Distillation via Kugelrohr (0.4 mm Hg, air bath, 180-190° C.) gave 54 g (81%) of the title compound as a light yellow liquid.

REFERENCE EXAMPLE 12 Preparation of 2-[6-(chloroformyl)hexyl]-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-1-one

To an ice-cold solution of 2-(6-carbodimethyl-t-butylsilyloxyhexyl)-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-1-one (92.7 g, 204 mmol) in tetrahydrofuran (283 ml) containing a catalytic amount of dimethylformamide (1.3 ml) is added freshly distilled oxalylchloride (19.3 ml,28.0 g, 221 mmol) via syringe (vigorous gas evolution, caution: carbon monoxide). The resulting mixture is stirred at 0° C. for 2 hours and at ambient temperature for two hours. The volatile material is removed in vacuo (bath 25° C., dry-ice/acetone cooled received, 0.4 mm final pressure). The resulting residue is slurried with hexane (900 ml), filtered through diatomaceous earth, followed by 100 ml hexane washing of the pool. The combined hexane solutions are concentrated in vacuo to give 72.5 g (99%) of the carboxylic acid chloride as a yellow liquid.

REFERENCE EXAMPLE 13 Preparation of 2-(7-oxo-8-hydroxyoctyl)-4-hydroxy-cyclopent-2-en-1-one

To the acid chloride of the previous example (72.5 g, 202 mmol) is added a solution of tris-trimethylsilyloxyethylene (130 g, 444 mmol) in 4A molecular sieve dried chlorobenzene (404 ml). The resulting solution is stirred at reflux under a nitrogen atmosphere for 4 hours. The solvent and excess reagent are evaporated in vacuo (final bath 60° C. 0.1 mm) to provide an amber oil (135 g).

The oil (135 g) is dissolved in tetrahydrofuran (1000 ml) and 1N aqueous HCl (200 ml) is added. The resulting mixture is stirred vigorously at reflux for 2 hours (caution: CO₂ evolution is rapid at first). The mixture is concentrated in vacuo to a volume of 400 ml, saturated with solid NaCl, and extracted with ethyl acetate (4 × 300 ml). The combined organic extracts are washed successively with brine (2 × 200 ml), 1:1 brine-saturated NaHCO₃ (2 × 200 ml) and brine 2 × 200 ml). The extract is dried over magnesium sulfate and K₂ CO₃ and filtered through diatomaceous earth. Evaporation in vacuo (using toluene chaser) gives 48.5 g of an off-white solid. The crude product is recrystallized from ethyl acetate (480 ml) and petroleum ether (240 ml) to give a first crop of 9.9 g (mg 57-62° C.). Three additional crops are obtained. All crops are combined to give 31.1 g (64%) of the title compound.

REFERENCE EXAMPLE 14 Preparation of 2-[7-oxo-8-(1-methoxy-1-methylethoxy)-octyl]-4-(1-methoxy-1-methylethoxy) cyclopent-2-en-1-one; [1-(1-methoxy-1-methylethoxy)- 8-[3-(1-methoxy-1-methylethoxy)-5-oxo-1-cyclopenten-1-yl]-octen-2-one]

To a stirred solution of 2-(7-oxo-1-hydroxyoctyl)-4-hydroxy cyclopent-2-en-1-one (31.2 g, 130 mmol) in sieve dried dichloromethane (190 ml) is added 2-methoxypropene (47 ml) followed by dichloroacetic acid (0.1 ml).

The resulting mild exotherm is maintained at 25° C. by water bath cooling. After 1 hour an additional charge of dichloroacetic acid (0.1 ml) is added. After a total of 2 hours, the solution is diluted with hexane (650 ml). The resulting solution is washed with saturated NaHCO₃ (50 ml) and brine and dried over magenesium sulfate/potassium carbonate and pyridine (0.05 ml) is added. The solvents are removed in vacuo to provide 48.4% (97%) of the title compound.

REFERENCE EXAMPLE 15

Treatment of the chloromethyl ketones or bromomethyl ketones of TABLE A with proparylmagnesium boromide by the procedure of Reference Example 3 is productive of the chloro and bromo alcohols of the Table. Treatment of these alcohols with chlorotrimethyl silane by the procedure of Reference Example 4 furnishes the corresponding chlorosilyl and bromosilyl ether. These sily ethers are converted to the respective vinyl stannane by the procedure described in Reference Example 5.

                                      TABLE A                                      __________________________________________________________________________     EXAMPLE                                                                               STARTING HALO KETONE                                                                            HALO ALCOHOL                                                                             HALO SILYL ETHER                                                                           PRODUCT VINYL                    __________________________________________________________________________                                                   STANNANE                          7     1-bromo-2-pentanone                                                                             4-bromomethyl-4-                                                                         4-bromomethyl-4-                                                                           1-tri-n-butylstannyl-4-                                  hydroxy-1-heptyne                                                                        trimethylsilory-                                                                           bromomethyl-4-trimethyl-                                           1-heptyne   silyloxy-trans-1-heptene          8     1-bromo-2-hexanone                                                                              4-bromomethyl-4-                                                                         4-bromomethyl-4-                                                                           1-tri-n-butylstannyl-4-                                  hydroxy-1-octyne                                                                         trimethylsiloxy-                                                                           bromomethyl-4-trimethyl-                                           1-octyne    silyloxy-trans-1-octene           9     1-bromo-2-heptanone                                                                             4-bromomethyl-4-                                                                         4-bromomethyl-4-                                                                           1-tri-n-butylstannyl-4-                                  hydroxy-1-nonyne                                                                         trimethylsiloxy-                                                                           bromomethyl-4-trimethyl-                                           1-nonyne    silyloxy-trans-1-nonene          10     1-bromo-2-octanone                                                                              4-bromomethyl-4-                                                                         4-bromomethyl-4-                                                                           1-tri-n-butylstannyl-4-                                  hydroxy-1-decyne                                                                         trimethylsiloxy-                                                                           bromomethyl-4-trimethyl-                                           1-decyne    silyloxy-trans-1-decene          11     1-chloro-2-pentanone                                                                            4-chloromethyl-4-                                                                        4-chloromethyl-4-                                                                          1-tri-n-butylstannyl-4-                                  hydroxy-1-heptyne                                                                        trimethylsiloxy-                                                                           chloromethyl-4-trimethyl-                                          1-heptyne   silyloxy-trans-1-heptene         12     1-chloro-2-heptanone                                                                            4-chloromethyl-4-                                                                        4-chloromethyl-4-                                                                          1-tri-n-butylstannyl-4-                                  hydroxy-1-nonyne                                                                         trimethylsiloxy-                                                                           chloromethyl-4-trimethyl-                                          1-nonyne    silyloxy-trans-1-nonene          13     1-chloro-2-octanone                                                                             4-chloromethyl-4-                                                                        4-chloromethyl-4-                                                                          1-tri-n-butylstannyl-4-                                  hydroxy-1-decyne                                                                         trimethylsiloxy-                                                                           chloromethyl-4-trimethyl-                                          1-decyne    silyloxy-trans-1-decene          __________________________________________________________________________

While specific embodiments of this invention have been described with particularity herein, it will be understood that the invention embraces all changes and modifications of the particular compounds chosen for purposes of illustration herein which do not depart from the spirit and scope of the invention.

TABLE B CYCLOPENTENONES

A. 2-(5-Carbotrimethylsiloxypent-2-cis-enyl-4-trimethylsiloxycyclopent-2-en-1-one

B. 2-(6-Carbotrimethylsiloxyhex-2-cis-enyl)-4-trimethylsiloxycyclopent-2-en-1-one

C. 2-(7-Carbotrimethylsiloxyhept-2-cis-enyl-4-trimethylsiloxycyclopent-2-en-1-one

D. 2-(5-Carbotrimethylsiloxypentyl)-4-trimethylsiloxycyclopent-2-en-1-one

E. 2-(6-Carbotrimethylsiloxyhexyl)4-trimethylsiloxycyclopent-2-en-1-one

F. 2-(7-Carbotrimethylsiloxyheptyl)-4-trimethylsiloxycyclopent-2-en-1-one

G. 2-(6-Carbotrimethylsiloxy-5-thia-hexyl)-4-trimethylsiloxycyclopent-2-en-1-one

H. 2-(6-Carbotrimethylsiloxy-5-oxa-hexyl)-4-trimethylsiloxycyclopent-2-en-1-one

I. 2-(6-Carbotrimethylsiloxyhex-2-cis-enyl)-4R-trimethylsiloxycyclopent-2-en-1-one

J. 2-6(-Carbotrimethylsiloxyhexyl)-4R-trimethylsiloxycyclopent-2-en-1-one

K. 2-(5-Carboethoxypent-2-cis-enyl)-cyclopent-2-en-1-one

L. 2-(6-Carboethoxyhex-2-cis-enyl)-cyclopent-2-en-1-one

M. 2-(7-Carboethoxyhept-2-cis-enyl)-cyclopent-2-en-1-one

N. 2-(5-Carboethoxypentyl)cyclopent-2-en-1-one

O. 2-(6-Carboethoxyhexyl)cyclopent-2-en-1-one

P. 2-(7-Carboethoxyheptyl)cyclopent-2-en-1-one

Q. 2-(6-Carboethoxy-5-thiahexyl)cyclopent-2-en-1-one

R. 2-(6-Carboethoxy-5-oxahexyl)cyclopent-2-en-1-one

TABLE I

Treatment of the appropriate cyclopentenones of Table B with the lithiocuprates derived from the vinylstannanes or vinyliodides of Reference Examples 5 and 14 by the procedure of Reference Example 6 is productive of the PGE₁ derivaters of Examples 1-44 of Table I.

Although in Tables I and II which follow the products are listed as dl,racemic products, when the cyclopentenones employed are optically active cyclopentenones (such as structure (14)), column or thin layer chromatography will provide the nat. 16α and nat. 16β compounds.

    __________________________________________________________________________     Ex-                                       PRODUCT PROSTAGLANDIN                ample                                                                              VINYL TIN            CYCLOPENTENONE   OF THE PGE1 SERIES                   __________________________________________________________________________     1   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carbotrimethylsiloxypentyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-heptene                                                                         4-trimethylsiloxycyclopent-2-en-                                                                20-nor-2-nor-13-trans                                                          prostenoic acid                                               1-one                                                 2   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carbotrimethylsiloxypentyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-octene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                2-nor-13-trans prostenoic acid                                1-one                                                 3   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carbotrimethylsiloxypentyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-nonene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                20-methyl-2-nor-13-trans                                                       prostenoic acid                                               1-one                                                 4   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carbotrimethylsiloxypentyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          4-trimethysiloxycyclopent-2-en-                                                                 20-ethyl-2-nor-13-trans                                                        prostenoic acid                                               1-one                                                 5   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-heptene                                                                         4-trimethylsiloxycyclopent-2-                                                                   20-nor-13-trans prostenoic                                                     acid                                                          1-one                                                 6   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-octene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                13-trans prostenoic acid                                      1-one                                                 7   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-nonene                                                                          4-trimethylsiloxycyclopent-2-en-1-one                                                           20-methyl-13-trans prostenoic                                                  acid                                                          1-one                                                 8   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                20-ethyl-13-trans prostenoic                                                   acid                                                          1-one                                                 9   1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carbotrimethylsiloxyheptyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-heptene                                                                         4-trimethylsiloxycyclopent-2-                                                                   20-nor-2-homo-13-trans                                                         prostenoic acid                                               1-one                                                 10  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carbotrimethylsiloxyheptyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-octene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                2-homo-13-trans prostenoic                                                     acid                                                          1-one                                                 11  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carbotrimethylsiloxyheptyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-nonene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                20-methyl-2-homo-13-trans                                                      prostenoic acid                                               1-one                                                 12  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carbotrimethylsiloxyheptyl)-                                                               dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          4-trimethylsiloxycyclopent-2-en-                                                                20-ethyl-2-homo-13-trans                                                       prostenoic acid                                               1-one                                                 13  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-heptene                                                                         thiahexyl)-4-trimethylsiloxy-                                                                   20-nor-3-thia-13-trans                                                         prostenoic acid                                               cyclopent-2-en-1-one                                  14  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-octene                                                                          thiahexyl)-4-trimethylsiloxy-                                                                   3-thia-13-trans prostenoic                                                     acid                                                          cyclopent-2-en-1-one                                  15  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-nonene                                                                          thiahexyl)-4-trimethylsiloxy-                                                                   20-methyl-3-thia-13-trans                                                      prostenoic acid                                               cyclopent-2-en-1-one                                  16  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          thiahexyl)-4-trimethylsiloxy-                                                                   20-ethyl-3-thia-13-trans                                                       prostenoic acid                                               cyclopent-2-en-1-one                                  17  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-heptene                                                                         oxahexyl)-4-trimethylsiloxy-                                                                    20-nor-3-oxa-13-trans                                                          prostenoic acid                                               cyclopent-2-en-1-one                                  18  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-octene                                                                          oxahexyl)-4-trimethylsiloxy-                                                                    3-oxa-13-trans prostenoic acid                                cyclopent-2-en-1-one                                  19  1-trans-tri-butylstannyl-4-chloromethyl-                                                            2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-nonene                                                                          oxahexyl)-4-trimethylsiloxy-                                                                    20-methyl-3-oxa-13-trans                                                       prostenoic acid                                               cyclopent-2-en-1-one                                  20  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxy-5-                                                                    dl-11a,16-dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          oxahexyl)-4-trimethylsiloxy-                                                                    20-ethyl-3-oxa-13-trans                                                        prostenoic acid                                               cyclopent-2-en-1-one                                  21  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl-                                                                 nat-11a,16-dihydroxy-9-oxo-16-ch                                               loromethyl-                              4-trimethylsiloxy-1-heptene                                                                         4R-trimethylsiloxy-                                                                             20-nor-13-trans prostenoic                                                     acid                                                          cyclopent-2-en-1-one                                  22  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                nat-11a,16-dihydroxy-9-oxo-16-ch                                               loromethyl-                              4-trimethylsiloxy-1-octene                                                                          4R-trimehylsiloxycyclopent-2-                                                                   13-trans prostenoic acid                                      en-1-one                                              23  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                nat-11a,16-dihydroxy-9-oxo-16-ch                                               loromethyl-                              4-trimethylsiloxy-1-nonene                                                                          4R-trimethylsiloxycyclopent-2-                                                                  20-methyl-13-trans prostenoic                                                  acid                                                          en-1-one                                              24  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carbotrimethylsiloxyhexyl)-                                                                nat-11a,16dihydroxy-9-oxo-16-chl                                               oromethyl-                               4-trimethylsiloxy-1-decene                                                                          4R-trimethylsiloxycyclopent-2-                                                                  20-ethyl-13-trans prostenoic                                                   acid                                                          en-1-one                                              25  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carboethoxypentyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-heptene                                                                         cyclopent-2-en-1-one                                                                            20-nor-2-nor-13-trans                                                          prostenoic acid                      26  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carboethoxypentyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-octene                                                                          cyclopent-2-en-1-one                                                                            2-nor-13-trans prostenoic acid       27  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carboethoxypentyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-nonene                                                                          cyclopent-2-en-1-one                                                                            20-methyl-2-nor-13-trans                                                       prostenoic acid                      28  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(5-carboethoxypentyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-decene                                                                          cyclopent-2-en-1-one                                                                            20-ethyl-2-nor-13-trans                                                        prostenoic acid                      29  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxyhexyl)-                                                                         dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-heptene                                                                         cyclopent-2-en-1-one                                                                            20-nor-13-trans prostenoic                                                     acid                                 30  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxyhexyl)-                                                                         dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-octene                                                                          cyclopent-2-en-1-one                                                                            13-trans prostenoic acid             31  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxyhexyl)-                                                                         dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-nonene                                                                          cyclopent-2-en-1-one                                                                            20-methyl-13-trans prostenoic                                                  acid                                 32  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxyhexyl)-                                                                         dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-decene                                                                          cyclopent-2-en-1-one                                                                            20-ethyl-13-trans prostenoic                                                   acid                                 33  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carboethoxyheptyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-heptene                                                                         cyclopent-2-en-1-one                                                                            20-nor-2-homo-13-trans                                                         prostenoic acid                      34  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carboethoxyheptyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-octene                                                                          cyclopent-2-en-1-one                                                                            2-homo-13-trans prostenoic                                                     acid                                 35  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carboethoxyheptyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-nonene                                                                          cyclopent-2-en-1-one                                                                            20-methyl-2-homo-13-trans                                                      prostenoic acid                      36  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(7-carboethoxyheptyl)-                                                                        dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-decene                                                                          cyclopent-2-en-1-one                                                                            20-ethyl-2-homo-13-trans                                                       prostenoic acid                      37  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-thiahexyl)-                                                                  dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-heptene                                                                         cyclopent-2-en-1-one                                                                            20-nor-3-thia-13-trans                                                         prostenoic acid                      38  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-thiahexyl)-                                                                  dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-octene                                                                          cyclopent-2-en-1-one                                                                            3-thia-13-trans prostenoic                                                     acid                                 39  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-thiahexyl)-                                                                  dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-nonene                                                                          cyclopent-2-en-1-one                                                                            20-methyl-3-thia-13-trans                                                      prostenoic acid                      40  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-thiahexyl)-                                                                  dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-decene                                                                          cyclopent-2-en-1-one                                                                            20-ethyl-3-thia-13-trans                                                       prostenoic acid                      41  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-oxahexyl)-                                                                   dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-heptene                                                                         cyclopent-2-en-1-one                                                                            20-nor-3-oxa-13-trans                                                          prostenoic acid                      42  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-oxahexyl)-                                                                   dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-octene                                                                          cyclopent-2-en-1-one                                                                            3-oxa-13-trans prostenoic acid       43  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-oxahexyl)-                                                                   dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-nonene                                                                          cyclopent-2-en-1-one                                                                            20-methyl-3-oxa-13-trans                                                       prostenoic acid                      44  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                          2-(6-carboethoxy-5-oxahexyl)-                                                                   dl-16-hydroxy-9-oxo-16-chloromet                                               hyl-                                     4-trimethylsiloxy-1-decene                                                                          cyclopent-2-en-1-one                                                                            20-ethyl-3-oxa-13-trans                                                        prostenoic acid                      __________________________________________________________________________

Treatment of the PGE₁ derivatives of Examples 1-44 of Table I with sodium borohydride by the procedure of Reference Example 7 is productive of the PGF.sub.α and PGF.sub.β derivatives of Examples 45 to 88 of Table I.

    ______________________________________                                                Starting Prostaglandin of                                                                       Product Prostaglandin of                               Example                                                                               the PGE Series   the PGF1a Series                                       ______________________________________                                         45     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-nor-2-                                                                       chloromethyl-20-nor-2-nor-                                    nor-13-trans prostenoic                                                                         13-trans prostenoic acid                                      acid                                                                    46     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-2-nor-13-                                                                       chloromethyl-2-nor-13-                                        trans prostenoic acid                                                                           trans prostenoic acid                                  47     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-methyl-2-                                     methyl-2-nor-13-trans                                                                           nor-13-trans prostenoic                                       prostenoic acid  acid                                                   48     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-ethyl-2-                                                                     chloromethyl-20-ethyl-2-                                      nor-13-trans prostenoic                                                                         nor-13-trans prostenoic                                       acid             acid                                                   49     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-nor-13-                                                                      chloromethyl-20-nor-13-                                       trans prostenoic acid                                                                           trans prostenoic acid                                  50     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-13-trans                                                                        chloromethyl-13-trans                                         prostenoic acid  prostenoic acid                                        51     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-methyl-                                       methyl-13-trans prostenoic                                                                      13-trans prostenoic acid                                      acid                                                                    52     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-ethyl-                                                                       chloromethyl-20-ethyl-                                        13-trans prostenoic acid                                                                        13-trans prostenoic acid                               53     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-nor-2-                                                                       chloromethyl-20-nor-2-                                        homo-13-trans prostenoic                                                                        homo-13-trans prostenoic                                      acid             acid                                                   54     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-2-homo-                                                                         chloromethyl-2-homo-13-                                       13-trans prostenoic acid                                                                        trans prostenoic acid                                  55     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-methyl-2-                                     methyl-2-homo-13-trans                                                                          homo-13-trans prostenoic                                      prostenoic acid  acid                                                   56     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-ethyl-                                                                       chloromethyl-20-ethyl-2-                                      2-homo-13-trans prostenoic                                                                      homo-13-trans prostenoic                                      acid             acid                                                   57     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-nor-3-                                                                       chloromethyl-20-nor-3-                                        thia-13-trans prostenoic                                                                        thia-13-trans prostenoic                                      acid             acid                                                   58     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-3-thia-13-                                                                      chloromethyl-3-thia-13-                                       trans prostenoic acid                                                                           trans prostenoic acid                                  59     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-methyl-3-                                     methyl-3-thia-13-trans                                                                          thia-13-trans prostenoic                                      prostenoic acid  acid                                                   60     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-ethyl-3-                                      ethyl-3-thia-13-trans                                                                           thia-13-trans prostenoic                                      prostenoic acid  acid                                                   61     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-nor-3-                                                                       chloromethyl-20-nor-3-oxa-                                    oxa-13-trans prostenoic                                                                         13-trans prostenoic acid                                      acid                                                                    62     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trhihydroxy-16-                                  16-chloromethyl-3-oxa-13-                                                                       chloromethyl-3-oxa-13-                                        trans prostenoic acid                                                                           trans prostenoic acid                                  63     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-                                                                             chloromethyl-20-methyl-3-                                     methyl-3-oxa-13-trans                                                                           oxa-13-trans prostenoic                                       prostenoic acid  acid                                                   64     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9a,11a,16-trihydroxy-16-                                   16-chloromethyl-20-ethyl-                                                                       chloromethyl-20-ethyl-                                        3-oxa-13-trans prostenoic                                                                       3-oxa-13-trans prostenoic                                     acid             acid                                                   65     nat-11a,16-dihydroxy-9-                                                                         nat-9a,11a,16-trihydroxy-                                     oxo-16-chloromethyl-20-                                                                         16-chloromethyl-20-nor-13-                                    nor-13-trans prostenoic                                                                         trans prostenoic acid                                         acid                                                                    66     nat-11a,16-dihydroxy-9-                                                                         nat-9a,11a,16-trihydroxy-                                     oxo-16-chloromethyl-13-                                                                         16-chloromethyl-13-trans                                      trans prostenoic acid                                                                           prostenoic acid                                        67     nat-11a,16-dihydroxy-9-                                                                         nat-9a,11a,16-trihydroxy-                                     oxo-16-chloromethyl-20-                                                                         16-chloromethyl-20-                                           methyl-13-trans prostenoic                                                                      methyl-13-trans prostenoic                                    acid             acid                                                   68     nat-11a,16-dihydroxy-9-                                                                         nat-9a,11a,16-trihydroxy-                                     oxo-16-chloromethyl-20-                                                                         16-chloromethyl-20-                                           ethyl-13-trans prostenoic                                                                       ethyl-13-trans prostenoic                                     acid             acid                                                   ______________________________________                                                Starting Prostaglandin of                                                                       Product Prostaglandin of                               Example                                                                               the PGE Series   the 11-deoxy PGF1a Series                              ______________________________________                                         69     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-nor-2-nor-                                                                      chloromethyl-20-nor-2-nor-                                    13-trans prostenoic acid                                                                        13-trans prostenoic acid                               70     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-2-nor-13-                                                                          chloromethyl-2-nor-13-                                        trans prostenoic acid                                                                           trans prostenoic acid                                  71     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-methyl-2-                                                                       chloromethyl-20-methyl-2-                                     nor-13-trans prostenoic                                                                         nor-13-trans prostenoic                                       acid             acid                                                   72     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-ethyl-2-                                                                        chloromethyl-20-ethyl-2-                                      nor-13-trans prostenoic                                                                         nor-13-trans prostenoic                                       acid             acid                                                   73     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-nor-13-                                                                         chloromethyl-20-nor-13-                                       trans prostenoic acid                                                                           trans prostenoic aicd                                  74     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-13-trans-                                                                          chloromethyl-13-trans                                         prostenoic aicd  prostenoic acid                                        75     dl-16-hydroyx-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-methyl-                                                                         chloromethyl-20-methyl-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               76     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-ethyl-13-                                                                       chloromethyl-20-ethyl-13-                                     trans prostenoic acid                                                                           trans prostenoic acid                                  77     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-nor-2-                                                                          chloromethyl-20-nor-2-                                        homo-13-trans prostenoic                                                                        homo-13-trans prostenoic                                      acid             acid                                                   78     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-2-homo-13-                                                                         chloromethyl-2-homo-13-                                       trans prostenoic acid                                                                           trans prostenoic acid                                  79     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-methyl-                                                                         chloromethyl-20-methyl-                                       2-homo-13-trans prostenoic                                                                      2-homo-13-trans prostenoic                                    acid             acid                                                   80     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-ethyl-                                                                          chloromethyl-20-ethyl-2-                                      2-homo-13-trans prostenoic                                                                      homo-13-trans prostenoic                                      acid             acid                                                   81     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-nor-3-                                                                          chloromethyl-20-nor-3-                                        thia-13-trans prostenoic                                                                        thia-13-trans prostenoic                                      acid             acid                                                   82     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-3-thia-13-                                                                         chloromethyl-3-thia-13-                                       trans prostenoic acid                                                                           trans prostenoic acid                                  83     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-methyl-                                                                         chloromethyl-20-methyl-                                       3-thia-13-trans prostenoic                                                                      3-thia-13-trans prostenoic                                    acid             acid                                                   84     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-ethyl-                                                                          chloromethyl-20-ethyl-                                        3-thia-13-trans prostenoic                                                                      3-thia-13-trans prostenoic                                    acid             acid                                                   85     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-nor-3-oxa-                                                                      chloromethyl-20-nor-3-oxa-                                    13-trans prostenoic acid                                                                        13-trans prostenoic acid                               86     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-3-oxa-13-                                                                          chloromethyl-3-oxa-13-                                        trans prostenoic acid                                                                           trans prostenoic acid                                  87     dl-16-hydroxy-9-oxo-16-                                                                         dl-9a,16-dihydroxy-16-                                        chloromethyl-20-methyl-                                                                         chloromethyl-20-methyl-                                       3-oxa-13-trans prostenoic                                                                       3-oxa-13-trans prostenoic                                     acid             acid                                                   88     dl-16-hydroxy-9-oxo-16                                                                          dl-9a,16-dihydroxy-16-                                        chloromethyl-20-ethyl-                                                                          chloromethyl-20-ethyl-                                        3-oxa-13-trans prostenoic                                                                       3-oxa-13-trans prostenoic                                     acid             acid                                                   ______________________________________                                    

Treatment of the PGE₁ derivatives of Examples 1-44 of Table I with lithium perhydro-9b-borophenalyl hydride by the procedure of Reference Example 8 is productive of the PGF₁α derivatives of Examples 89-132 of Table I.

    ______________________________________                                                Starting Prostaglandin Of                                                                       Product Prostaglandin Of                               Example                                                                               The PGE Series   The PGF1B Series                                       ______________________________________                                         89     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       2-nor-13-trans   2-nor-13-trans                                                prostenoic acid  prostenoic acid                                        90     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-2-nor-                                                                          16-chloromethyl-2-nor-                                        13-trans prostenoic acid                                                                        13-trans prostenoic acid                               91     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-2-nor-13-trans                                                                           methyl-2-nor-13-trans                                         prostenoic acid  prostenoic acid                                        92     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     2-nor-13-trans   2-nor-13-trans                                                prostenoic acid  prostenoic acid                                        93     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               94     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-13-trans                                                                        16-chloromethyl-13-trans                                      prostenoic acid  prostenoic acid                                        95     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-13-trans  methyl-13-trans                                               prostenoic acid  prostenoic acid                                        96     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     13-trans prostenoic acid                                                                        13-trans prostenoic acid                               97     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl- 16-chloromethyl-                                              20-nor-2-homo-13-trans                                                                          20-nor-2-homo-13-trans                                        prostenoic acid  prostenoic acid                                        98     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-2-homo-                                                                         16-chloromethyl-2-homo-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               99     dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-methyl-                                                                      16-chloromethyl-20-methyl-                                    2-homo-13-trans  2-homo-13-trans                                               prostenoic acid  prostenoic acid                                        100    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     2-homo-13-trans  2-homo-13-trans                                               prostenoic acid  prostenoic acid                                        101    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       3-thia-13-trans  3-thia-13-trans                                               prostenoic acid  prostenoic acid                                        102    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-3-thia-                                                                         16-chloromethyl-3-thia-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               103    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-methyl-                                                                      16-chloromethyl-20-methyl                                     3-thia-13-trans  3-thia-13-trans                                               prostenoic acid  prostenoic acid                                        104    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl                                      3-thia-13-trans  3-thia-13-trans                                               prostenoic acid  prostenoic acid                                        105    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       3-oxa-13-trans   3-oxa-13-trans-                                               prostenoic acid  prostenoic acid                                        106    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-3-oxa-                                                                          16-chloromethyl-3-oxa                                         13-trans prostenoic acid                                                                        13-trans prostenoic acid                               107    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-methyl-                                                                      16-chloromethyl-20-methyl-                                    3-oxa-13-trans   3-oxa-13-trans                                                prostenoic acid  prostenoic acid                                        108    dl-11a,16-dihydroxy-9-oxo-                                                                      dl-9B,11a,16-trihydroxy-                                      16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     3-oxa-13-trans   3-oxa-13-trans                                                prostenoic acid  prostenoic acid                                        109    nat-11a,16-dihydroxy-9-                                                                         nat-9B,11a,16-trihydroxy-                                     oxo-16-chloromethyl-                                                                            16-chloromethyl-                                              20-nor-13-trans  20-nor-13-trans                                               prostenoic acid  prostenoic acid                                        110    nat-11a,16-dihydroxy-9-                                                                         nat-9B,11a,16-trihydroxy-                                     oxo-16-chloromethyl-                                                                            16-chloromethyl-                                              13-trans prostenoic acid                                                                        13-trans prostenoic acid                               111    nat-11a,16-dihydroxy-9-                                                                         nat-9B,11a,16-trihydroxy-                                     oxo-16-chloromethyl-                                                                            16-chloromethyl-                                              20-methyl-13-trans                                                                              20-methyl-13-trans                                            prostenoic acid  prostenoic acid                                        112    nat-11a,16-dihydroxy-9-                                                                         nat-9B,11a,16-trihydroxy-                                     oxo-16-chloromethyl-                                                                            16-chloromethyl-                                              20-ethyl-13-trans                                                                               20-ethyl-13-trans                                             prostenoic acid  prostenoic acid                                                                Product Prostaglandin Of                                      Starting Prostaglandin Of                                                                       The 11-Deoxy                                           Example                                                                               The PGE Series   PGF1B Series                                           ______________________________________                                         113    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           nor-2-nor-13-trans                                                                              nor-2-nor-13-trans                                            prostenoic acid  prostenoic acid                                        114    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-2-nor-                                                                          16-chloromethyl-2-nor-                                        13-trans prostenoic acid                                                                        13-trans prostenoic acid                               115    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-2-nor-13-trans                                                                           methyl-2-nor-13-trans                                         prostenoic acid  prostenoic acid                                        116    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     2-nor-13-trans   2-nor-13-trans                                                prostenoic acid  prostenoic acid                                        117    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               118    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl- 16-chloromethyl-                                              13-trans prostenoic acid                                                                        13-trans prostenoic acid                               119    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-13-trans  methyl-13-trans                                               prostenoic acid  prostenoic acid                                        120    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     13-trans prostenoic acid                                                                        13-trans prostenoic acid                               121    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-nor-                                                                         16-chloromethyl-20-nor-                                       2-homo-13-trans  2-homo-13-trans                                               prostenoic acid  prostenoic acid                                        122    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-2-homo-                                                                         16-chloromethyl-2-homo-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               123    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-2-homo-13-trans                                                                          methyl-2-homo-13-trans                                        prostenoic acid  prostenoic acid                                        124    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-ethyl-                                                                       16-chloromethyl-20-ethyl-                                     2-homo-13-trans  2-homo-13-trans                                               prostenoic acid  prostenoic acid                                        125    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           nor-3-thia-13-trans                                                                             nor-3-thia-13-trans                                           prostenoic acid  prostenoic acid                                        126    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-3-thia-                                                                         16-chloromethyl-3-thia-                                       13-trans prostenoic acid                                                                        13-trans prostenoic acid                               127    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-3-thia-13-trans                                                                          methyl-3-thia-13-trans                                        prostenoic acid  prostenoic acid                                        128    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           ethyl-3-thia-13-trans                                                                           ethyl-3-thia-13-trans                                         prostenoic acid  prostenoic acid                                        129    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           nor-3-oxa-13-trans                                                                              nor-3-oxa-13-trans                                            prostenoic acid  prostenoic acid                                        130    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-3-oxa-                                                                          16-chloromethyl-3-oxa-                                        13-trans prostenoic acid                                                                        13-trans prostenoic acid                               131    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           methyl-3-oxa-13-trans                                                                           methyl-3-oxa-13-trans                                         prostenoic acid  prostenoic acid                                        132    dl-16-hydroxy-9-oxo-                                                                            dl-9B,16-dihydroxy-                                           16-chloromethyl-20-                                                                             16-chloromethyl-20-                                           ethyl-3-oxa-13-trans                                                                            ethyl-3-oxa-13-trans                                          prostenoic acid  prostenoic acid                                        ______________________________________                                    

TABLE II

Treatment of the appropriate cyclopentenones of Table B with the lithicuprates derived from the vinylstannanes or vinyliodides of Reference Examples 5 and 15 by the procedure of Reference Example 6 is productive of the PGE₁ derivatives of Examples 1-28 of Table II.

    __________________________________________________________________________                                                PRODUCT PROSTAGLANDIN OF            EX.                                                                               VINYL TIN           CYCLOPENTENONE      THE PGE2 SERIES                     __________________________________________________________________________     1  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carbotrimethylsiloxypent-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-heptene                                                                        4-trimethylsiloxycyclopent-2-en-1-one                                                              20-nor-2-nor-5-cis-13-trans                                                    protadienoic acid                   2  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carbotrimethylsiloxypent-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-octene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              2-nor-5-cis-13-trans                                                           prostadienoic                                                                  acid                                3  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carbotrimethylsiloxypent-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-nonene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-methyl-2-nor-5-cis-13-trans                                                 N                                                                              prostadienoic acid                  4  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carbotrimethylsiloxypent-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-decene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic                                                                  acid                                5  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-heptene                                                                        4-trimethylsiloxycyclopent-2-en-1-one                                                              20-nor-5-cis-13-trans                                                          prostadienoic acid                  6  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-octene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              5-cis-13-trans-prostadienoic                                                   acid                                7  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-nonene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-methyl-5-cis-13-trans                                                       prostadienoic                                                                  acid                                8  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-decene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-ethyl-5-cis-13-trans                                                        prostadienoic acid                  9  1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-heptene                                                                        4-trimethylsiloxycyclopent-2-en-1-one                                                              20-nor-2-homo-5-cis-13-trans                                                   prostadienoic                                                                  acid                                10 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-octene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              2-homo-5-cis-13-trans                                                          prostadienoic acid                  11 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-nonene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-methyl-2-homo-5-cis-13-trans                                                O                                                                              prostadienoic acid                  12 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-                                                         dl-11a,16-dihydroxy-9-oxo-16-                                                  chloromethyl-                          4-trimethylsiloxy-1-decene                                                                         4-trimethylsiloxycyclopent-2-en-1-one                                                              20-ethyl-2-homo-5-cis-13-trans                                                 prostadienoic acid                  13 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          nat-11a,16-dihydroxy-9-oxo-16-                                                 chloromethyl-                          4-trimethylsiloxy-1-heptene                                                                        4R-trimethylsiloxycyclopent-2-en-1-one                                                             20-nor-5-cis-13-trans                                                          prostadienoic acid                  14 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          nat-11a,16-dihydroxy-9-oxo-16-                                                 chloromethyl-                          4-trimethylsiloxy-1-octene                                                                         4R-trimethylsiloxycyclopent-2-en-1-one                                                             5-cis-13-trans prostadienoic                                                   acid                                15 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          nat-11a,16-dihydroxy-9-oxo-16-                                                 N                                                                              chloromethyl-                          4-trimethylsiloxy-1-nonene                                                                         4R-trimethylsiloxycyclopent-2-en-1-one                                                             20-methyl-5-cis-13-trans                                                       prostadienoic acid                  16 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-                                                          nat-11a,16-dihydroxy-9-oxo-16-                                                 O                                                                              chloromethyl-                          4-trimethylsiloxy-1-decene                                                                         4R-trimethylsiloxycyclopent-2-en-1-one                                                             20-ethyl-5-cis-13-trans                                                        prostadienoic                       __________________________________________________________________________                                                acid                                                                           PRODUCT PROSTAGLANDIN OF            EX.                                                                               VINYL TIN           CYCLOPENTENONE      11-DEOXY PGE2                       __________________________________________________________________________                                                SERIES                              17 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carboethoxypent-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-heptene                                                                        cyclopent-2-en-1-one                                                                               20-nor-2-nor-5-cis-13-trans                                                    prostadienoic                                                                  acid                                18 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carboethoxypent-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-octene                                                                         cyclopent-2-en-1-one                                                                               2-nor-5-cis-13-trans                                                           prostadienoic acid                  19 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carboethoxypent-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-nonene                                                                         cyclopent-2-en-1-one                                                                               20-methyl-2-nor-5-cis-13-trans                                                 O                                                                              prostadienoic acid                  20 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(5-carboethoxypent-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-decene                                                                         cyclopent-2-en-1-one                                                                               20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic acid                  21 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carboethoxyhex-2-cis-enyl)                                                                    dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-heptene                                                                        cyclopent-2-en-1-one                                                                               20-nor-5-cis-13-trans                                                          prostadienoic acid                  22 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carboethoxyhex-2-cis-enyl)                                                                    dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-octene                                                                         cyclopent-2-en-1-one                                                                               5-cis-13-trans prostadienoic                                                   acid                                23 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carboethoxyhex-2-cis-enyl)                                                                    dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-nonene                                                                         cyclopent-2-en-1-one                                                                               20-methyl-5-cis-13-trans                                                       prostadienoic acid                  24 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(6-carboethoxyhex-2-cis-enyl)                                                                    dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-decene                                                                         cyclopent-2-en-1-one                                                                               20-ethyl-5-cis-13-trans                                                        prostadienoic acid                  25 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carboethoxyhept-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-heptene                                                                        cyclopent-2-en-1-one                                                                               20-nor-2-homo-5-cis-13-trans                                                   prostadienoic                                                                  acid                                26 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carboethoxyhept-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-octene                                                                         cyclopent-2-en-1-one                                                                               2-homo-5-cis-13-trans                                                          prostadienoic acid                  27 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carboethoxyhept-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-nonene                                                                         cyclopent-2-en-1-one                                                                               20-methyl-2-homo-5-cis-13-trans                                                prostadienoic acid                  28 1-trans-tri-n-butylstannyl-4-chloromethyl-                                                         2-(7-carboethoxyhept-2-cis-enyl)                                                                   dl-16-hydroxy-9-oxo-16-chlorome                                                thyl-                                  4-trimethylsiloxy-1-decene                                                                         cyclopent-2-en-1-one                                                                               20-ethyl-2-homo-5-cis-13-trans                                                 A                                                                              prostadienoic                       __________________________________________________________________________                                                acid                           

Treatment of the PGE.sub.α derivatives of Examples 1-28 of Table II with sodium borohydride by the procedure of Reference 7 is productive of the PGF.sub.α and PGF.sub.β derivatives of Examples 29 to 56 of Table II.

    ______________________________________                                              Starting Prostaglandin Of                                                                        Product Prostaglandin Of                                Ex.  The PGE Series    The PGF2a Series                                        ______________________________________                                         29   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      30   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-2-nor-                                                                           16-chloromethyl-2-nor-                                       5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      31   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      32   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      33   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      34   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-5-cis-                                                                           16-chloromethyl-5-cis-                                       13-trans          13-trans                                                     prostadienoic acid                                                                               prostadienoic acid                                      35   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      36   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      37   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      38   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-2-homo-                                                                          16-chloromethyl-2-homo-                                      5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      39   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      40   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9a,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      41   nat-11a,16-dihydroxy-9-                                                                          nat-9a,11a,16-trihydroxy-                                    oxo-16-chloromethyl-                                                                             16-chloromethyl-                                             20-nor-5-cis-13-trans                                                                            20-nor-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      42   nat-11a,16-dihydroxy-9-                                                                          nat-9a,11a,16-trihydroxy-                                    oxo-16-chloromethyl-                                                                             16-chloromethyl-                                             5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      43   nat-11a,16-dihydroxy-9-                                                                          nat-9a,11a,16-trihydroxy-                                    oxo-16-chloromethyl-                                                                             16-chloromethyl-                                             20-methyl-5-cis-13-trans                                                                         20-methyl-5-cis-13-trans                                     prostadienoic acid                                                                               prostadienoic acid                                      44   nat-11a,16-dihydroxy-9-                                                                          nat-9a,11a,16-trihydroxy-                                    oxo-16-chloromethyl-                                                                             16-chloromethyl-                                             20-ethyl-5-cis-13-trans                                                                          20-ethyl-5-cis-13-trans                                      prostadienoic acid                                                                               prostadienoic acid                                      45   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-  16-chloromethyl-                                             20-nor-2-nor-5-cis-13-trans                                                                      20-nor-2-nor-5-cis-13-trans                                  prostadienoic acid                                                                               prostadienoic acid                                      46   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-  16-chloromethyl-                                             2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      47   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      48   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      49   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      50   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-5-cis-                                                                           16-chloromethyl-5-cis-                                       13-trans          13-trans                                                     prostadienoic acid                                                                               prostadienoic acid                                      51   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      52   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      53   dl-16-hydroxy-9-oxo-                                                                             cl-9a,16-dihydroxy-                                          16-chloromethyl-20-                                                                              16-chloromethyl-20-                                          nor-2-homo-5-cis-13-trans                                                                        nor-2-homo-5-cis-13-trans                                    prostadienoic acid                                                                               prostadienoic acid                                      54   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-2-                                                                               16-chloromethyl-2-                                           homo-5-cis-13-trans                                                                              homo-5-cis-13-trans                                          prostadienoic acid                                                                               prostadienoic acid                                      55   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      56   dl-16-hydroxy-9-oxo-                                                                             dl-9a,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      ______________________________________                                    

Treatment of the PGE.sub.α derivatives of Example 1-28 of Table II with lithium perhydro-9b-boraphenalyl hydride by the procedure of Reference Example 8 is productive of the PGF₁α derivatives of Examples 57-84 of Table II.

    ______________________________________                                              Starting Prostaglandin Of                                                                        Product Prostaglandin Of                                Ex.  The PGE Series    The PGF2B Series                                        ______________________________________                                         57   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      58   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-2-nor-                                                                           16-chloromethyl-2-nor-                                       5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      59   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      60   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      61   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-                                                                              16-chloromethyl-20-                                          nor-5-cis-13-trans                                                                               nor-5-cis-13-trans                                           prostadienoic acid                                                                               prostadienoic acid                                      62   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-5-                                                                               16-chloromethyl-5-                                           cis-5-13-trans    cis-5-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      63   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      64   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      65   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor                                       2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      66   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-2-homo-                                                                          16-chloromethyl-2-homo-                                      5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      67   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      68   dl-11a,16-dihydroxy-9-oxo-                                                                       dl-9B,11a,16-trihydroxy-                                     16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      69   nat-11a,16-dihydroxy-9-                                                                          nat-9B,11a,16-trihydroxy-                                    oxo-16-chloromethyl-20-                                                                          16-chloromethyl-20-                                          nor-5-cis-13-trans                                                                               nor-5-cis-13-trans                                           prostadienoic acid                                                                               prostadienoic acid                                      70   nat-11a,16-dihydroxy-9-                                                                          nat-9B,11a,16-trihydroxy-                                    oxo-16-chloromethyl-5-                                                                           16-chloromethyl-5-                                           cis-13-trans      cis-13-trans                                                 prostadienoic acid                                                                               prostadienoic acid                                      71   nat-11a,16-dihydroxy-9-                                                                          nat-9B,11a,16-trihydroxy-                                    oxo-16-chloromethyl-20-                                                                          16-chloromethyl-20-                                          methyl-5-cis-13-trans                                                                            methyl-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      72   nat-11a,16-dihydroxy-9-oxo-                                                                      nat-9B,11a,16-trihydroxy-                                    16-chloromethyl-20-                                                                              16-chloromethyl-20-                                          ethyl-5-cis-13-trans                                                                             ethyl-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      73   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-nor                                                                           16-chloromethyl-20-nor-                                      2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      74   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-2-nor-                                                                           16-chloromethyl-2-nor-                                       5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      75   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      76   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-nor-5-cis-13-trans                                                                             2-nor-5-cis-13-trans                                         prostadienoic acid                                                                               prostadienoic acid                                      77   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      78   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-  16-chloromethyl-                                             5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      79   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      80   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    5-cis-13-trans    5-cis-13-trans                                               prostadienoic acid                                                                               prostadienoic acid                                      81   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-nor-                                                                          16-chloromethyl-20-nor-                                      2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      82   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-2-                                                                               16-chloromethyl-2-                                           homo-5-cis-13-trans                                                                              homo-5-cis-13-trans                                          prostadienoic acid                                                                               prostadienoic acid                                      83   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-methyl-                                                                       16-chloromethyl-20-methyl-                                   2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      84   dl-16-hydroxy-9-oxo-                                                                             dl-9B,16-dihydroxy-                                          16-chloromethyl-20-ethyl-                                                                        16-chloromethyl-20-ethyl-                                    2-homo-5-cis-13-trans                                                                            2-homo-5-cis-13-trans                                        prostadienoic acid                                                                               prostadienoic acid                                      ______________________________________                                     

What is claimed is:
 1. An optically active compound of the formula: ##STR15## wherein Y is ##STR16## X is ##STR17## R₁ is hydrogen or hydroxyl; R₂ is hydrogen or C₁ to C₆ alkyl;R₃ is chloromethyl and bromomethyl; R₄ is hydrogen and C₁ to C₃ alkyl; Z is selected from the group consisting of a divalent moiety of the formula --(CH₂)_(n) --, --(CH₂)_(m) OCH₂ -- and --(CH₂)_(m) SCH₂ -- wherein n is 5 to 7 and M is 3 to 5 and the racemic mixture thereof, and when R₁ is hydrogen, the pharmaceutically acceptable salts thereof.
 2. A compound according to claim 1 wherein R₃ is --CH₂ Cl.
 3. The racemic compounds according to claim 2, 11α,16-dihydroxy-9-oxo-16-chloromethyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 4. The optically active compounds according to claim 2, nat. 11α,16-dihydroxy-9-oxo-16-chloromethyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 5. The optically active compound according to claim 4, nat. 11α,16-dihydroxy-9-oxo-16-chloromethyl-13 trans prostenoic acid, methyl ester. 